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9.2Microorganisms and Infection

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9.2.1

What Is an Infection?

From a human-centric standpoint, "infection" can be defined as a phenomenon in which pathogenic organisms invade human bodies to settle there. If the process causes illness as a result, it is regarded as an infectious disease. However, microorganisms including bacteria do not usually cause illness just by settling in the body. This depends largely on the relationships between the individual organisms and humans, but is mainly attributable to the properties of microorganisms and the biological defense responses of humans. There are varying species of microorganisms, each of which has its distinctive way of infection, settlement, and sometimes virulence.
The surface and inside of the human body are inhabited by innumerable microorganisms. Although some of them cause an infectious disease by infection alone, many just remain dormant, barring special cases such as when the immune function of the host has deteriorated. Diverse varieties of resident bacteria exist, ranging from the ones in the digestive tracts, which rather than just settling there, actively play useful roles in humans, to the ones which are simply overlooked by the human immune system by staying outside the immunological barrier, e.g., skin and membrane. Resident bacteria can conceivably cause infectious diseases if either they enter the body in profusion due to injuries etc., or the immune function is weakened so much that it cannot eliminate the incursion of bacteria in the oral cavity or intestinal tracts into the bloodstream, irrespective of their number.
Human pathogenic microorganisms are classified roughly into bacteria, fungi, and viruses*1. The vast majority of bacteria involved in human diseases are eubacteria, whereas archaea do not normally infect humans. Despite the common belief, a number of infectious diseases are caused by fungi. Although viruses are not usually regarded as living organisms, they are also important pathogens that cause infectious diseases. Here, we will elaborate on the classification and characteristics of microorganisms in connection with the general perspective of microbiology as well as with infectious diseases.

*1 As pathogenic microorganisms, the majority of fungi that cause infectious diseases are classified as fungoid. Although viruses are not exactly organisms, they are treated as microorganisms in this chapter for the sake of expediency.

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9.2.2

Bacterial Infection

Bacteria cause numerous infectious diseases such as tonsillitis, pneumonia, diarrhea, meningitis, cystitis, and tuberculosis. Of these, some are associated with a particular bacterial species (e.g., dysentery), whereas many have several causative bacteria. In other words, clinical symptoms of bacterial infections differ depending on where they occur. Figure 9-1A shows the basic structure of a bacterium. Since bacteria are prokaryotes, they do not possess nuclei. As pathogenic microorganisms, bacteria have been classified in accordance with the connection between clinical conditions/states of patients and microscopic observation. Staining bacterial cells using a technique called Gram's method results in their cell walls being dyed (purple) in Gram-positive bacteria (e.g., Staphylococcus aureus), but not dyed (red) in Gram-negative bacteria (e.g., Escherichia coli). Those that are dyed by acid-fast staining are acid-fast bacteria (e.g., tubercle bacillus). These are all based on the differences in the properties of bacterial cell walls, which are inseparably connected to their clinical states and treatment.

Fig. 9-1. Structures of a Bacterium and a Fungus

(A) A bacterium is a prokaryote in which the nucleus is not covered by a nuclear envelope. It has a macromolecular membrane called a capsule outside the plasma membrane and cell wall. The capsule has the function to protect the bacterial body from the immune system of the host. The structure of the cell wall varies widely depending on the species of bacteria with the flagellum being absent in some species.
(B) A fungus is a eukaryote with subcellular organelles enclosed by membranes within the cytoplasm. Aside from the yeast-type form depicted in the figure, the structures of fungi include the mycelial form, which takes a thin thread-like shape. Some fungi have dimorphic properties, which enable them to alternate between both forms.

Infection-causing bacteria produce enzymes and toxins (Fig. 9-2A). The production of proteolytic enzymes destroys the tissues in the proximity of the sites of bacterial settlement. Cholera toxin secreted by Vibrio cholerae acts on small intestinal cells to make them secrete an excessive amount of fluid, thereby inducing intense diarrhea. Clostridium tetani, the causative bacterium of tetanus, produces a toxin that disrupts the signal transduction between nerves and muscles, perpetually straining the muscles. Obstruction to the respiratory muscles leads to death.
In contrast to toxins secreted extracellularly by cells, which is called exotoxins, some are produced intracellularly, called endotoxins. These are contained in the cell walls of Gram-negative bacteria, and their effects become conspicuous after the cells are obliterated by treatment or immune response. Since exotoxins strongly activate the immune responses of various cells, blood infection by Gram-negative bacteria often elicit shocks*2 to the subjects as a consequence of an excessive immune response. Infiltration into cells is another major factor in the virulence of bacterial infection (Fig. 9-2B). Shigellae, for instance, induce phagocytosis by mucosal cells in the large intestine with proteins secreted from them, thereby entering the cells. Once inside the cells, they proliferate and spread to adjacent cells. This process destroys the mucosal cells, causing hemorrhage.

Fig. 9-2. Virulence of Bacteria

(A) Exotoxins secreted by a bacterium damage adjacent cells and disrupt the homeostasis of the host cell.
(B) After infiltrating the host cell, the bacterium is incorporated into the cell to proliferate there or destroy the cell.

*2 Slight abnormalities in the circulation of peripheries cause damage to the important organs, leading to disorder in the blood circulation throughout the body. This is a grave condition that poses a threat to life.

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Antibiotics

Antibiotics are substances produced by microorganisms. Since some of them are antitumorogenic rather than antibacterial, "antibiotics" used for the treatment of infectious diseases are essentially antibacterial agents. As mentioned in the beginning of this chapter, the first antibacterial agent to be discovered was penicillin.
Antibacterial agents inhibit proliferation of bacteria or act antiseptically without affecting human cells. This is because they target exclusively bacteria-specific structures and enzymes to exert efficacy so as to minimize side effects to humans. Their action mechanisms include inhibition of bacterial cell wall synthesis, inhibition of bacterial protein synthesis, inhibition of nucleic acid synthesis necessary for bacterial growth, and inhibition of folic acid metabolism.
For example, penicillin is an inhibitory agent for cell wall synthesis, which binds to a part of the cell wall synthesized by a bacterium, thereby preventing the cell wall from elongating further. As the pressure within bacteria is kept extremely high, inability to form the cell wall causes the bacterium to rupture, leading to its death. From time to time, however, variants with slight differences in the cell wall structure can emerge from the same species of bacteria. Since penicillin is unable to bind to the cell walls of such variants, they can grow in a normal manner even in the presence of the antibiotic. The variants are penicillin-resistant bacteria. Besides, bacteria with penicillin-decomposing activity are also known to exist.
Aside from resistance to cell wall synthesis inhibitor, the emergence of bacteria resistant to other antibacterial drugs, e.g., ones that can decompose antibacterials and ones that have a strong mechanism to pump out antibacterials extracellularly, is posing problems to medical fields. The examples are methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multidrug-resistant Pseudomonas aeruginosa (MDRP), and multidrug-resistant tuberculosis (MDR-TB). Emerging successively, they pose a serious threat.

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9.2.3

Fungal Infection

Fungi are eukaryotes; hence, looking from the evolutionary process, they are higher species than bacteria. They consist not only of unicellular species but also multicellular ones (Fig. 9-1B). Environment abounds with fungi. Fermentation of liquor, bread, and cheese is done by a fungus called yeast. Despite the existence of these good fungi, fungal infectious diseases are fomenting trouble in medical fields by causing severe infections among patients with weakened immune functions. Athlete's foot is a fungal infectious disease and presumably affects the most number of people. The virulence of fungi derives primarily from enzymes destroying tissues and fungal bodies proliferating to embolize small and midsize blood vessels, thereby causing cellular necrosis. They do not produce exotoxins*3 as commonly as bacteria.

*3 Although it is not strictly in line with the topic of infectious diseases, a toxin called aflatoxin produced by Aspergillus flavus, a type of mold, is a carcinogen causing hepatic cell cancer.

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Tuberculosis

A number of historical characters have died from tuberculosis: Okita Soshi, Masaoka Shiki, Hiuguchi Ichiyo, Miyazawa Kenji, and Taki Rentaro, etc. Many artists have succumbed to the disease in the Meiji and Taisho periods, so it has sometimes gone so far as to be considered as a subject of adoration as it evoked the image of the illness contracted by geniuses. On the other hand, it used to be abhorred as the "illness that ruins the country" or "haibyo (lung illness)." If a family member came down with the lung illness, the entire family would be discriminated by people around them, negatively affecting their employment and marriage prospects. This kind of situation continued until the end of the Second World War. Even now, a few number of people scowl at the mere mention of tuberculosis; we have often seen people getting overdefensive and trying to deny or hide the truth when they are asked in clinics about their previous or family history of the disease.
This discriminatory notion toward tuberculosis derives conceivably from the fact that it is a transmissible and refractory disease. Tuberculosis treatment back in the times when there were no antituberculous medications, comprised nothing but rest, health resort therapy for many years, and nutritional therapy, whose effects are all limited. Sanatoriums for tuberculosis patients were built at secluded places. Patients with pulmonary tuberculosis would sometimes vomit blood, while Pott's disease patients (spinal tuberculosis) would writhe in fierce agony.
Today, several antituberculous drugs have appeared and the basic treatment methods have been established. In addition, it has become practical to test the sensitivity of a tubercle bacillus to antituberculous drugs (efficacy), making it possible for many patients to recoup normal lives before the contraction of the disease in a comparatively short period of time after the start of a treatment. The average treatment period is between 6 months and 1 year. Since tuberculosis is transmitted through airborne infection, it is prone to cause an outbreak. Strict infection control measures are therefore taken in case of tubercle bacilli detected in the phlegm of patients etc. Nonetheless, improvement in the knowledge of infection prevention has drastically changed the situation that people used to isolate patients haphazardly out of fear.
The emergence of antituberculous drugs and the improvement in hygiene conditions have finally eradicated tuberculosis—or so it seemed. In fact, the number of tuberculosis patients has started showing an increasing tendency again recently. This may be attributed to the declining awareness of the disease among medical personnel and society, accompanied by new group infection cases. Besides, the increase in senior citizens may have contributed to a rise in the number of patients among those with weakened immune functions. Moreover, tubercule bacilli on which antituberculous drugs have little effect are increasing, which creates challenges for the future. As in this case, when an infectious disease, once regarded as a relic of the past, reemerges and starts influencing society again owing to changes in social circumstances or the causative microorganism, the disease is classified as a reemerging infectious disease. We hope that correct knowledge and an appropriate handling of tuberculosis would help reduce the disease and discrimination.

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9.2.4

Viral Infection

Although viruses have a nucleic acid and a protein enclosing it, they lack the ability to proliferate on their own; instead, they utilize the organelles of a host cell to proliferate after infection. Even though viruses are not living organisms, they are usually treated as the same manner as bacteria and fungi because they are transmissible among individuals and sometimes cause diseases. Most common colds, influenza, chickenpox, measles, and AIDS are caused by viruses. Viruses are considered to have played pivotal roles in the evolution of species as the carriers of genes, but we digress—and entrust this discussion to other books.
Unless it enters a host cell, a virus can neither proliferate nor display its virulence. They normally enter human bodies via the mucous membranes or blood. Each virus has high affinity for a specific organ, into which it is incorporated to proliferate. This is how hepatitis viruses cause hepatitis and Japanese encephalitis viruses cause encephalitis. After infecting cells, viruses act in various ways as shown in Table 9-1, serving as factors to signify the characteristics of diseases. Human immunodeficiency virus (HIV; the causative virus of AIDS) selectively infects a certain type of cells responsible for immune functions. It kills a host cell after proliferation. Consequently, it depletes the group of immune cells, thus rendering the host immunocompromised. Although a hepatitis B virus does not destroy hepatic cells, infected hepatic cells are eliminated by the immune cells of the host, which causes hepatitis. Viruses do not affect their hosts by producing toxins as bacteria do; the symptoms of viral infectious diseases are induced by diverse immune responses generated by viral infections.

Table 9-1. Effects of Viral Infection on Cells

These modes are not necessarily fixed to individual viruses; they are subject to change depending on the condition of the viruses and cells.

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Humans and Avian Influenza

An avian influenza virus was detected in a patient who died from pneumonia in Hong Kong, 1997. This provoked quite a stir because avian flu had been believed not to infect humans at that time. The unrest spread due to not only its discovery in a human but also the strong virulence of the strain and the fear of a pandemic. Since then, there have been many reports of avian flu infection cases in humans. Diagnostic statistics obtained by the WHO in 2007 reported 85 confirmed cases, of which 58 had died. There are several types of avian influenza, of which we will discuss those with a high virulence in this column.
In determining the virulence of viruses, the questions of where they infect and to what extent they proliferate are important indices. Avian flu viruses do not normally infect humans since they find it difficult to bind to the surface of mucosal cells in the human respiratory tract, which surface serves as the portal for viral infections. The surface of the intestinal mucosa of birds is expressing molecules that facilitate avian flu viruses to bind. They therefore infect from there and then proliferate. Meanwhile, it has been revealed that molecules to facilitate the binding of equine influenza viruses are being expressed within and near the alveolus of the bronchiole*4 in the periphery of the human respiratory tract. If avian flu viruses manage to reach this far through one pathway or another, they are able to settle deep inside the lung. The fact that they are apt to invade the peripheries of the lung might have something to do with their predisposition to cause serious conditions complicated with pneumonia etc.
Similar to other viruses, influenza viruses also proliferate by exploiting host cells. In the case of ordinary human influenza viruses, they are confined in the respiratory tract and the epithelial cells of the intestinal tract, thus limiting proliferation to these parts. In contrast, all the enzymes needed for proliferation of avian flu viruses are expressed in almost all cells, making it possible for the viruses to proliferate throughout the body. Consequently, the conditions are more likely to be exacerbated further.
At present, avian influenza is not particularly contagious to humans. Nevertheless, influenza viruses have the characteristics to acquire completely different properties through gene recombination with other types of influenza viruses, and change their natures through mutations in their own genes. This implies the probability that a mutated avian flu virus with an ability to frequently infect humans, that is to say a "new type of influenza virus," may emerge. As one of the scenarios of the emergence of a new type of influenza virus, attention has been focused on roles to be played by pigs. Pigs are known to get infected with human influenza viruses; concurrently, it is believed that avian influenza viruses can also easily bind to the mucosa of the respiratory tract of pigs. Since pig farming is performed in many regions throughout the world, humans have a plenty of opportunities to come into contact with pigs. This means that avian and human influenza viruses may have a chance to exchange their genes, or worse, that might have happened already. A recombinant avian influenza virus could have acquired an ability to easily infect humans while retaining its high virulence, thus contributing to the emergence of a new type of human influenza virus.
Currently, efforts are underway to develop human vaccines against avian influenza viruses, but their actual efficacy has not been substantiated yet. Historically, correlation is believed to exist between major pandemics of influenza and changes in the types of influenza viruses. In light of the fact that no human groups have immunity against any new types of viruses, no individual is likely to be immune to a new influenza virus either. An emergence of such a virus, therefore, might trigger a massive pandemic.

*4 An airway for respiration. The trachea diverges into right and left bronchi, each of which continues diverging into bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts, alveolar sacs, and finally, alveoli (diverging 23 times in humans). Pathogenic microorganisms do not normally reach the peripheries of the respiratory tract due to the ciliary motion of the mucosa and the immunological effect.

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9.2.5

Mechanism from Infection until the Onset of Symptoms

A process in which infection induces systemic symptoms is explained below by referring to an example of fever (Fig. 9-3). Sensing the occurrence of an infection, cells responsible for immunity such as leukocytes release a variety of signal molecules. Some of the molecules act on the thermoregulation system in an effort to maintain higher body temperatures, thereby causing fever. Although fever is considered to be an effective biological defense response in eliminating infected viruses etc., excessive fever does more harm than good as it brings about the loss of bodily strength as well as organ injuries. Molecules such as interferons are involved in the onset of other symptoms accompanied by fever such as lumbago and arthralgia.
The discussions so far have been focused on the roles played by pathogenic microorganisms in infection. As has often been mentioned, however, infection is a phenomenon inextricable from the response of host organisms. In the next section, we will explain the mechanism of immunity—the biological defense response of host organisms.

Fig. 9-3. Mechanism of Fever

In cases of respiratory tract infection, pathogenic microorganisms such as bacteria and viruses invade the body from the mucous membranes of the respiratory tract, which serve as airways during respiration. Once the pathogenic microorganisms establish an infection through their settlement and proliferation, cells responsible for immunity initiate the production of proteins called cytokines, e.g., interleukins (IL-1 and IL-6), tumor necrosis factors (TNF), and interferons. These cytokines promote the synthesis of a substance called prostaglandin E2 (PGE2), which in turn causes fever as a systemic reaction. Besides, these cytokines are also involved in arthralgia experienced during fever.

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Relationship between Autoimmune Disorders and Infectious Diseases

In general, an autoimmune disorder is a disease whose onset is deeply associated with the aberrant immune functions of an organism, resulting in the immune system attacking its own body. An infectious disease, on the other hand, is induced by exogenous pathogenic microorganisms. The body's immune system is activated in response to these microorganisms in an attempt to get rid of them. Although autoimmune disorders and infectious diseases are seemingly two completely different conditions, they are closely connected via the immune system of individual organisms.
Rheumatoid arthritis is one of the most frequent autoimmune disorders. It is a disease in which connective tissues, such as tissues in joints, are damaged by leukocytes etc., to cause inflammation, leading to the destruction of the tissues. In addition to painkillers and anti-inflammatories, immunosuppressants can also be chosen as medications. In recent years, molecular target drugs that act directly on cytokines etc., pertaining to inflammation processes have been developed (see Column in Section 4 of Chapter 7). One such drug is infliximab, which binds to a cytokine called TNF-α to inhibit its original action (Column Fig. 9-1). While involved in the pathogenesis of inflammation in tissues, TNF-α plays an important role in the pathology of rheumatism. It has become a blessing for patients with rheumatoid arthritis, since conventional medications never helped produce sufficient effects.

Column Fig. 9-1. Action of TNF-α


That said, the fact that infliximab interferes with the immune system naturally entails effects of something other than of improving the symptoms of rheumatoid arthritis. Shortly after the start of the use of the drug in the United States, the country filed a series of reports on the cases of tuberculosis, witnessing an approximately quadruple rise in the risk of contracting the disease. Ordinarily, even if tubercle bacilli enter the body, tuberculosis actually develops in not more than 10% of the time. To put it another way, people who are not certain if they have ever contracted the disease can possess the tubercle bacilli in their bodies. Inside the body, such bacteria are confined by the immune system so as not to be active there, and TNF-α plays a pivotal role in this process. Although not much has been revealed, it is postulated that inhibiting the action of TNF-α may spur the activity of dormant tubercle bacilli in the body. Today, prior to the use of infliximab in patients, measures such as evaluating the risk of developing tuberculosis and administering concomitant medications to prevent the disease are being taken.

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The Survival Strategy of HIV

Apoptosis (see Column in Section 2 of Chapter 7) is important not only in biogenesis and maintaining homeostasis but also in infection and biological defense. In some instances, however, the mechanism of apoptosis, which should normally be beneficial to organisms, can be exploited by the extraneous enemies of the organisms.
HIV, the causative virus of AIDS, is one such example. AIDS is a disease in which, accompanied by the progress of its symptoms, the number of a type of T lymphocytes responsible for immunity in the blood decreases, thus rendering the infected person susceptible to various other infections. It had formerly been believed to be caused by the virus directly damaging T cells before the progress of research shed light on the tactful survival strategies adopted by HIV using apoptosis. After infecting T cells, HIV proliferates within the cells while synthesizing a wide array of virus-derived proteins, some of which are then secreted extracellularly to induce the apoptosis of other normal T cells. This causes the number of normal T cells, which should otherwise function to eliminate HIV, to decline, thus depriving them of their ability to prevent infection. Under such circumstances, however, the infected T cells would also undergo apoptosis, thus making it impossible for HIV itself to proliferate. In order to avoid this, HIV forces the infected T cells to produce a protein to prevent apoptosis signals from entering these infected cells in addition to other proteins such that it can gain time required for its proliferation.

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